Certain hexahydro-dibenzo [b,d] pyran-9-ones are known to be useful drugs. As described in U.S. Pat. Nos. 3,928,598, 3,944,673, and 3,953,603, d1-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hex ahydro-9H-dibenzo[b,d]pyran-9-one is of particular importance in the treatment of anxiety and depression. The preparation of such compounds suffer from being multistep and of low yields. Fahrenholtz, Lurie and Kierstead, J. Am. Chem. Soc. 88, 2079 (1966), 89, 5934 (1967), describe the synthesis of such hexahydro-dibenzo[b,d]pyranones by reaction of a 5-alkyl resorcinol with diethyl .alpha.-acetylglutarate to form an ethyl 4-methyl-5-hydroxy-7-alkylcoumarin-3-propionate, which compound is cyclized by reaction with a metal hydride to afford a 1-hydroxy-3-alkyl-7,10-dihydro-6H-dibenzo[b,d]-pyran-6,9 (8H)-dione. The latter compound is ketalized at the 9-position, and then reacted with methyl magnesium bromide to provide, after de-ketalization, a 1-hydroxy-3-alkyl-6,6-dimethyl-6a,7,8,9-tetrahydro-6H-dibenzo[b,d]-pyran-o ne, which upon reduction by lithium in ammonia provides predominantly the corresponding d1-trans-1-hydroxy-3-alkyl-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-diben zo[b,d]pyran-9-one, with minor quantities of the less active 6a,10a-cis isomer.
This invention relates to a one-step process for preparing substantially exclusively trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-di benzo[b,d]pyran-9-ones from 2,6-methano-2H-1-benzoxocin derivatives. While certain 2,6-methano-2H-1-benzoxocin derivatives are known, none have been used as intermediates in the preparation of dibenzopyranone compounds. Razdan et al., J. Am. Chem. Soc., 96 5860 (1974), reported the synthesis of 2-methyl-5-isopropylidene-7-hydroxy-9-pentyl-2,6-methano-3,4,5,6-tetrah ydro-2H-1-benzoxocin from the reaction between 5-pentyl resorcinol and 1-methyl-1-hydroxy-4-(2-propenyl)-2-cyclohexene. Such benzoxocin was reported not to be convertible to a dibenzopyran derivative. Additionally, Razdan and Zitko reported the conversion of 1-hydroxy-3-n-pentyl-6,6,9-trimethyl-6a.alpha.,7,8,10a.beta.-tetrahydro-6H -dibenzo[b,d]pyran to 2-methyl-5-isopropylidene-7-hydroxy-9-pentyl-2,6-methano-2H-1-benzoxocin, Tetrahedron Letters, 4947 (1969). These workers reported that the benzoxocin derivative is in equilibrium with the dibenzopyran derivative, but that such equilibrium heavily favors the benzoxocin. The efficient conversion of a 2,6-methano-2H-1-benzoxocin to a dibenzopyranone derivative has not heretofore been reported. An object of this invention is to provide a process for converting a 2H-1-benzoxocin to substantially exclusively a 6a,10a-trans-hexahydrodibenzopyranone.